Glucokinase (GK) (ATP: D-hexose 6-phosphotransferase, EC2.7.1.1) is one (hexokinase IV) of the four kinds of hexokinases of mammals. Hexokinase is an enzyme in the first stage of glycolysis system and catalyzes the reaction from glucose to glucose hexaphosphate.
Expression of glucokinase is limited mostly to liver and pancreatic beta cells and plays an important role in sugar metabolism by controlling the rate-determining step of glucose metabolism of those cells. Glucokinases of liver and pancreatic beta cells are different in sequences of N-terminal 15 amino acids as a result of difference in splicings but their enzymatic properties are same. In the three hexokinases (I, II and III) other than glucokinase, their enzymatic activity is saturated at the glucose concentration of not more than 1 mM while Km of glucokinase to glucose is 8 mM which is near the physiological blood sugar level.
Accordingly, from the normal blood sugar level (5 mM), an increase in intracellular glucose metabolism takes place via glucokinase in a mode which is correspondent to changes in blood sugar of postcibal blood sugar increase (10 to 15 mM).
With regard to a compound which is structurally related to the compounds of the present invention, a compound represented by the formula (A)
is, for example, described (refer, for example, to JP-T-2000-501914).
However, the compound represented by the above formula (A) has a methoxy group at 7-position of a quinazoline skeleton but the compound according to the present invention is different from the above in such a respect that it is hydrogen atom or fluorine atom. With regard to a compound where 7-position of a quinazoline skeleton is hydrogen or fluorine atom, there is no specific description therein.
With regard to a compound having a quinazoline skeleton and diabetes mellitus is mentioned as an object disease thereof, a compound represented by the formula (B)
is, for example, described (refer, for example, to JP-T-2002-536414). The compound represented by the above formula (B) is identical with the compound according to the present invention in such a respect that it has a quinazoline skeleton and has a methoxy group at 6-position of a quinazoline ring. However, the compound represented by the formula (B) has a hydroxyl group at 7-position of a quinazoline ring and a group bonding to an amino group bonded to 4-position of a quinazoline ring is different from that of the compound according to the present invention.